Bone is a dynamic tissue that constantly remodels by balancing osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The disruption of this tissue homeostasis causes several devastating human diseases including osteoporosis, arthritis and bone metastasis of cancers, leading to severe pain, fractures, life-threatening hypercalcemia, limited mobility and increased mortality. The nuclear receptor PPAR3 (peroxisome proliferator-activated receptor-3) is a critical regulator of energy metabolism and an important therapeutic target for treating the escalating obesity and diabetes epidemic. Emerging evidence suggests that PPAR3 also modulates bone turnover. We discovered that activation of PPAR3 promotes osteoclast differentiation and bone resorption. It has also been shown to suppress osteoblast differentiation and bone formation. Importantly, these findings unravel a central role for PPAR3 in the connection between mineral and energy metabolism, linking skeletal disorders such as osteoporosis with metabolic syndrome hallmarked by obesity, diabetes and atherosclerosis. Synthetic PPAR3 ligands thiazolidinediones (TZDs) are FDA-approved drugs for insulin resistance and type 2 diabetes. Recent clinical trials have reported that long-term use of TZDs increased fracture rates among diabetic patients. Thus, it is of paramount importance to understand how PPAR3 regulates bone metabolism. In this proposal, we hypothesize that 1) PPAR3 exerts a biphasic regulation of osteoclastogenesis, at both the early stage of osteoclast lineage commitment and the late stage of osteoclast differentiation; 2) this regulation is influenced by the metabolic context and represents a critical mechanism for TZD-mediated bone loss. In Aim 1, we will determine the cellular mechanisms for osteoclast development by identifying its hematopoietic origin. In Aim 2, we will determine the molecular mechanisms for osteoclast lineage commitment and PPAR3 regulation. In Aim 3, we will determine how TZDs induce bone loss in the context of diabetes. A combination of tools will be employed, including mouse genetic and disease models, molecular and cell biology, biochemistry and small molecules. The proposed investigation will elucidate how PPAR3 regulates mineral metabolism by controlling osteoclast lineage commitment, differentiation and function, as well as how this regulation is influenced by energy metabolism. It will open exciting new paths to the understanding of skeletal physiology and its connection with metabolic diseases. Importantly, the outcome of these studies will provide fundamental insights for the treatment of diabetes, as well as other diseases associated with increased bone resorption such as osteoporosis, arthritis and cancer metastasis. Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community.